Abstract
Spectroscopy is increasingly used to investigate and monitor the solid state forms of pharmaceutical materials and products. Spectroscopy's speed, non-destructive sampling, compatibility with fibre optics and safety also make it attractive for in-line monitoring.
In this thesis, the spectroscopic techniques Fourier transform Raman spectroscopy, terahertz pulsed spectroscopy and second harmonic generation were used to characterise and quantify polymorphism and crystallinity of pharmaceutical compounds. Where possible, the multivariate analysis technique partial least squares was used for quantitative analysis. Fourier transform Raman spectroscopy detects polarisability changes mainly associated with molecular vibrations. Terahertz pulsed spectroscopy is a new spectroscopic technique that operates between the infrared and microwave regions of the electromagnetic spectrum and detects dipole moment changes mainly associated with crystalline phonon vibrations in the solid state. Second harmonic generation is a nonlinear optical phenomenon that depends on the dipole moment in crystals and crystal symmetry.
Several materials capable of existing in different solid state forms were used. FT-Raman spectroscopy was able to differentiate carbamazepine forms I and III, enalapril maleate forms I and II and y-crystalline and amorphous indomethacin. Combined with partial least squares the technique could quantify binary mixtures of CBZ forms I and III with a limit of detection as low as 1 %, and mixtures of enalapril maleate with a limit of detection of as low as 2%.
Terahertz pulsed spectroscopy obtained very different spectra for carbamazepine forms I and III, enalapril maleate forms I and II, y-crystalline and amorphous indomethacin, crystalline and supercooled thermotropic liquid crystalline fenoprofen calcium, three forms of lactose, and five forms of sulphathiazole. At present the modes in the spectra cannot be attributed to specific phonon modes. Quantitation of binary mixtures of different forms of a compound using partial least squares analysis usually resulted in a limit of detection of about 1 %.
Second harmonic generation was used to quantify binary mixtures of different forms of enalapril maleate and lactose, as well as binary mixtures of enalapril maleate form II and polyvinylpyrrolidone. A quantitative relationship was present for each of the mixtures, however the limits of detection were usually above 10%. The high value is probably due to the machine being a prototype and univariate analysis associated with a single output variable. Future improvements to the apparatus and measurement parameters are likely to reduce the limits of detection. Ranitidine hydrochloride polymorphs could also be differentiated using second harmonic generation, however y-crystalline and amorphous indomethacin and forms I and III of carbamazepine could not.
The methods used in this thesis were successfully used for qualitative and quantitative analysis of polymorphism and crystallinity of pharmaceutical compounds. TPS and SHG are useful additions to the range of experimental techniques that can be used to investigate and monitor properties of pharmaceutical solids.